Structure-Based design of Marine-derived Meridianin C derivatives as glycogen synthase kinase 3β inhibitors with improved oral bioavailability: From aminopyrimidyl-indoles to the sulfonyl analogues

Shuwen Han; Wei Zhou; Chunlin Zhuang; Fener Chen

doi:10.1016/j.bioorg.2021.105537

Structure-Based design of Marine-derived Meridianin C derivatives as glycogen synthase kinase 3β inhibitors with improved oral bioavailability: From aminopyrimidyl-indoles to the sulfonyl analogues

Bioorg Chem. 2022 Feb:119:105537. doi: 10.1016/j.bioorg.2021.105537. Epub 2021 Dec 6.

Authors

Shuwen Han¹, Wei Zhou², Chunlin Zhuang³, Fener Chen⁴

Affiliations

¹ Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
² Department of Chemistry, Fudan University, Shanghai 200438, China.
³ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.
⁴ Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China. Electronic address: rfchen@fudan.edu.cn.

PMID: 34902644
DOI: 10.1016/j.bioorg.2021.105537

Abstract

Glycogen synthase kinase 3β (GSK-3β) has become an attractive target for the treatment of diabetes. Compound I is an indole-based GSK-3β inhibitor designed from the Meridianin C, a marine natural product (MNP) isolated from Aplidium meridianum. However, this compound has a moderate inhibitory activity toward GSK-3β (IC₅₀ = 24.4 μM), moderate glucose uptake (38%), and especially, a low oral bioavailability (F = 11.4%). In the present study, applying the structure-based design strategy, a series of derivatives modified on the indole moiety were synthesized based on the lead compound I, followed by evaluating their cytotoxic activity, antihyperglycemic activity, and kinase inhibitory activity. Among this series, compound 6x with a sulfonyl group displayed the highest glucose uptake (83.5%) in muscle L6 cells, showing much higher inhibitory activity against GSK-3β (IC₅₀ = 5.25 μM). Molecular docking indicated that compound 6x was properly inserted into the ATP-binding binding pocket of GSK-3β with a higher docking score (-8.145 kcal/mol) compared with that of compound I (-6.950 kcal/mol), interpreting the higher kinase inhibitory activity toward GSK-3β. Remarkably, compound 6x showed favorable drug-like properties, including significantly better oral bioavailability (F = 47.4%) and no two-week acute toxicity at a dose of 1 g/kg. Our findings suggest that these MNP-derived sulfonyl indole derivatives could be used as lead compounds for the development of anti-hyperglycemic drugs.

Keywords: Diabetes; GSK-3β; Glucose uptake; Inhibitor; Oral bioavailability; Structure-based optimization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Biological Availability
Cell Survival / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
Glycogen Synthase Kinase 3 beta / metabolism
Indoles / administration & dosage
Indoles / chemistry
Indoles / metabolism
Indoles / pharmacology*
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / administration & dosage
Pyrimidines / metabolism
Pyrimidines / pharmacology*
Rats
Structure-Activity Relationship
Urochordata / chemistry

Substances

Indoles
Protein Kinase Inhibitors
Pyrimidines
meridianin C
Glycogen Synthase Kinase 3 beta